UBASH3A deficiency accelerates type 1 diabetes development and enhances salivary gland inflammation in NOD mice
Year: 2020
Type: article
Abstract: Recent advances in genetic analyses have significantly refined human type 1 diabetes (T1D) associated loci. The goal of such effort is to identify the causal genes and have a complete understanding of the molecular pathways that independently or interactively influence cellular processes leading to the destruction of insulin producing pancreatic β cells. UBASH3A has been suggested as the underlying gene for a human T1D associated region on chromosome 21. To further evaluate the role of UBASH3A in T1D, we targeted Ubash3a in NOD mice using zinc-finger nuclease mediated mutagenesis. In both 10-week-old females and males, significantly more advanced insulitis was observed in UBASH3A-deficient than in wild-type NOD mice. Consistently, UBASH3A-deficient NOD mice developed accelerated T1D in both sexes, which was associated with increased accumulation of β-cell autoreactive T cells in the spleen and pancreatic lymph node. Adoptive transfer of splenic T cells into NOD.Rag1-/- mice demonstrated that UBASH3A deficiency in T cells was sufficient to promote T1D development. Our results provide strong evidence to further support a role of UBASH3A in T1D. In addition to T1D, UBASH3A deficiency also promoted salivary gland inflammation in females, demonstrating its broad impact on autoimmunity.
Source: Scientific Reports
Institutions: Medical College of Wisconsin, University of Iowa
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,870
Awards: Shaping diabetogenic T cells by IL-27 in type 1 diabetes, G5904669230, Cytokines driving T cell dysregulation in lacrimal gland autoimmunity, Discovery and Functional Studies of Genes for T1D GWAS Susceptibility Loci, Mechanistic and therapeutic role of the CD137-CD137L axis in Type 1 Diabetes
OpenAlex ID: W3043828248